Urea derivatives of dodecahydro-5,9-methanobenzocyclooctenes

ABSTRACT

Substituted dodecahydro-5,9-methanobenzocyclooctenes of the formula I:   wherein R1, R2, R3 and X are as defined below. These compounds are useful as anti-arrhythmic agents.

United States Patent Merrill [151 -3,689,528 1451' Sept. 5, 1972 (54] UREA DERIVATIVES OF I DODECAHYDRO-5,9-

METHANOBENZOCYCLOOCTENES [72] Inventor: Edward J. Merrill, Whippany, NJ.

[73] Assignee: Warner-Lambert Pharmaceutical Company, Morris Plains, NJ.

[22] Filed: Jan. 7, 1970 [21] Appl. No.: 1,290

Related US. Application Data [52] US. Cl ..260/482 C, 260/295 T, 260/471 C,

260/553 R, 260/553 A, 260/563 P, 260/617 F, 260/999, 424/300, 424/322 [51] Int. Cl ..C07c 125/06 [58] Field of Search ..260/482 C, 482 B, 617 F [5 6] References Cited OTHER PUBLICATIONS Chem. Abstract 5123470, Noller, Chem. of Organic Cmpds. 2nd Ed., pp. 315

Primary Examiner-Lorraine A. Weinberger Assistant Examiner-Paul J. Killos Att0rneyAlbert H, Graddis, Henry E. Millson, -Jr.,

Frank S. Chow, Neil D. Edwards and Anne M. Kelly [57] ABSTRACT Substituted -dodecahydro-S,9-methanobenzocycloocv tenes of the formula I:

I 1 !l ]l0 1 x 2 11 11 mN-o -x on 111 o o 5 4 I R3 11 H RzNC x hcr/w 11) 7 3 v wherein R R R and X are as defined below. These compounds are useful as anti-arrhythmic agents.

4 Claims, No Drawings UREA DERIVATIVES OF DODECAHYDRO-S ,9-

METHANOBENZOCYCLOOCTENES This application is a divisional application of U.S. Ser. No. 678,162, now U.S. Pat. No. 3498993 filed Oct. 24, 1967, which is in turn a continuation-in-part appli- 5 cation of U.S. Ser. No. 401,978, filed Oct. 6, 1964, now abandoned.

This invention relates to compositions of matter and more particularly this invention relates to substituted wherein R represents hydrogen, lower alkyl of one to six carbons such as methyl, ethyl, propyl, isopropyl, etc., pentamethylene, phenyl or aralkyl such as phenyl lower alkyl; R represents hydrogen, lower alkyl of one to six carbons such as methyl, ethyl, propyl, isopropyl, etc., phenyl or aralkyl such as phenyl lower alkyl; R, is hydrogen or hydroxy and n is an integer of 1 or 2, and X is oxygen (O-) or -NH. The symbols R R and i n as used hereinafter have the same meaning as defined.

This invention also includes within its scope a novel process for the production of the above compounds as well as intermediates obtained during their synthesis.

The compounds of this invention exhibit potent antiarrhythmic activity and because of this activity they are useful in the treatment of cardiac arrthythmia in mammals.

The compounds of this invention have an oral LD between 400 mg/kg to greater than 1,000 mg/kg in mice. The ED using the Harris et a1. technique for measuring anti-arrhythmic activity described in Am. J. Physiol. 163 505 (1950), is between 5 to 30 mg/kg in dogs. Examples of the pharmacological profile of the compounds of this invention are tabulated below:

Based on reversal of ventricular arrhythmias to a normal sinus rhythm using the coronary ligation technique of Harris and Kokernot, Am. J. Physiol. 163 505 (1950).

Generally speaking, a dose of about 300 to 500 mg may be administered orally or by injection to a mammalian host weighing about kg in treating cardiac arrhythmias. The dosage requirements may be adjusted according to variation in body weight and variation in individual requirements according to methods known to the healing arts. Among the dosage forms which the compounds of this invention may be administered are for example, tablets, capsules, injectables, and the like.

These dosage forms are compounded according to the pharmacists art with inert pharmaceutical carriers such as lactose, water, terra alba, and the like.

These compounds may be administered either alone or in combination with other known therapeutic agents which will enhance their therapeutic spectrum such as tranquilizers and sedatives, for example, chlordiazepoxide, phenobarbital; coronary vasodilators such as pentaenthyritol tetranitrate; diuretics such as chlorothiazide, and the like.

According to this invention the above compounds are produced by reacting a compound of the formula:

The reduction may be effected at ice bath temperature such as 0 to 5 C. The starting compound A is prepared according to a procedure described by Barbulescue, Rev. Chim. (Bucharest) 7, 45 (1956) CA. 51, 3740 (1957). Briefly, cyclohexanone in alcohol is treated with an aldehyde of the formula R,CHO at about C. to obtain this starting material.

Compound B may then be treated with R -isocyanate, in an anhydrous solvent such as dry benzene, toluene or xylene at a temperature of 20 to 30 C. Compound B, if reacted with 1 mol of the R -isocyanate yields the desired compound of this invention wherein n is 1, whereas reacting with 2 mols or greater of R -isocyanate produces the desired compound wherein n is 2.

EXAMPLE 1 Dodecahydro-5,9-methano-10-methylbenzocycloocten-4a,l l-diol 1 l-(N-methylcarbamate) To a vigorously stirred solution of 22.4 g. (0.1 mol) dodecahydro-S ,9-methano- 1 O-methylbenzocycloocten-4 a,l1-dio1 in 500 cc dry benzene is added a solution of 5.53 g. (0.1 mol) methyl isocyanate in 270 cc dry benzene over 30 minutes. The solution is stirred at 20 to 30 C for 18-24 hours then refluxed for 5 hours. The solvent is stripped and the residual oil is triturated with 50 cc petroleum ether, cooled and the solid filtered. This is recrystallized from 50% aqueous EtOl-l to give 16.3 g. (58 percent) of dodecahydro-5,9-methano- 10-methylbenzocyc1oocten-4a,1 1 -diol 1 1 -(N-methy1- carbamate) as a colorless solid melting at 124-126 C. IR (Nujol) 3580, 3250, 1710, 1685, 1560, 1260, 1140, 1000.

Analysis for C H No z Calc: C 68.30 H 9.67 N 4.99 Found: C 68.58 H 9.82 N 4.95

EXAMPLE 2 '10 g. (60 percent) of dodecahydro-5,9-methano-10- methylbenzocyc1oocten-4a, 1 1-diol( 2,5-dimethylallophanate) as a colorless solid, melting at 147149 C. IR (Nujol) 3350,3300, 1715, 1660, 1530, 1270, 1200, 1160, 1010; NMR (CDC1 0.9 and 1.0 (C-CH 2.6 (tert.OH), 2.8 and 2.9 (NHC 3), 3.2 (NCH 8.5 (NH).

Analysis for C ,H N,O,:

Calc.: C 63.88 H 8.93 N 8.28 Found: C 64.12 H 9.07 N 8.43

EXAMPLE 3 Dodecahydro-S ,9-methano-10-methylbenzocycloocten-4a,] l-diol 1 l-carbamate To a suspension of 2.25 g (10 mM) dodecahydro- 5 ,9-methano--methylbenzocycloocten-4a, 1 l-diol and 1.30 g sodium isocyanate in 20 ml of dry benzene, is added a solution of 1.55 ml trifluoroacetic acid in 5 ml of dry benzene and the suspension is stirred at room temperature overnight. Ten milliliters of water are added and the resulting precipitate is filtered. The solid is recrystallized from equal parts of abs. ethanol and anhyd. ether, to give 1.0 g (37.5 percent) of the desired dodecahydro-S,9-methano--methylbenzocycloocten-4a,11-diol ll-carbamate, melting at 263265 C. IR (Nujol) 3500, 3350, 1705, 1600, 1405, 1050, 960, 940

Analysis for C H NO 1,2,3,4,4a(or 10)5,6,7,8,9-Decahydro-5,9-methano- IO-methylbenzocycloocten-l 1 -ol carbamate Gaseous HC is bubbledthrough a suspension of 2.24 g 10mM) dodecahydro-5,9-methano-10-methylbenzocycloocten-4a,1 l-diol and 1.30 g (20 mM) dried sodium isocyanate in 25 ml dry CHCl for min. then allowed to stir at room temperature overnight. Ten milliliters of H 0 are added and the reaction mixture is extracted with ether. On removal of the solvent, the residue is recrystallized from acetonitrile to give the product which melts at 140146 C. IR (mull) 3500, 3220, 1710, 1590, 1400, 1320, 1125, 1030. The NMR indicates that this compound is a mixture of double bond isomers.

Analysis for C H NO Calc: C 72.25 H 9.30 N 5.62 Found: C 72.38 H 9.40 N 5.40

EXAMPLE 5 Dodecahydro-5,9-methano-1 O-methylbenzocylcoocten-4a,1 l-diol 1 1-(3-pyridine carbamate) To a suspension of 1.20 g. (10 mM) 3-pyridyl isocyanate in 25 ml dry benzene is added 2.24 g (10 mM) dodecahydroS ,9-methano-10-methylbenzocycloocten- 4a,l l-diol in 50 ml dry benzene. The resulting suspension is refluxed for 1 hr. and the solvent is removed. The resulting solid is recrystallized from cyclohexane to give 1.7 g (50 percent) of the product, melting at l55l57 C. IR (mull) 3600, 3200, 1730, 1600, 1550, 1425, 1410,1370,1215, 1050,1020.

Analysis for cz HznNzoai Calc: C 69.74

Found: C 70.01

EXAMPLE 6 l 1 -Amino-dodecahydro-5 ,9-methano-10-methylbenzocyclooctene hydrochloride To a solution of 1 1.1 g (50 mM) of dodecahydro-5,9- methanol O-methylbenzocycloocten-4a-o1 1 1 one in 7.9 ml. of formamide heated to 170 C. is added 6.4 ml mM) of formic acid in five portions and the reaction mixture is stirred for 2 hrs. after each addition. The mixture is cooled and 7.5 ml of cone HC is added and the temperature again raised to C. When the excess reagents have boiled away, there remains a solid which when recryst. from abs. ethanol and anhydrous ether gives 6.09 g (50 percent) of the product melting at 270 C. (d).

Analysis for C H N'HCI Calc: C 68.97

Found: C 69.00

EXAMPLE 7 1 Dodecahydro5,9-methanol O-methylbenzocycloocten- 1 1 -y1 )-3-methylurea To a stirred solution of 5.2 g (25 mM) of 11- aminododecahydro-S ,9-methano-10-methylbenzocyclooctene in 125 ml dry C H is added a solution of 1.38 g (25 mM) of methyl isocyanate in 67 ml dry C H dropwise over 30 minutes. The resulting suspension is stirred at RT. overnight then refluxed for 5 hours. The solid filtered and recrystallized from carbon tetrachloride to give one isomer of the desired compound melting at 189192 C. (lsomer A). When the filtrate from the reaction is evaporated to dryness and the resulting solid recrystallized from carbon tetrachloride, another isomer of the desired compound is obtained melting at 194-196 C. (lsomer B). 1R (mull) lsomer A: 3250, 1655, 1535, 1410, 1270, 1165, 1115. IR (mull) lsomer B: 3250, 1660, 1540, 1410, 1270,1160,1110

Analysis for o l-amp;

Cale: C 72.68 H 10.67 N 10.60 Found (lsomer A) C 72.98 H 10.70 N 10.36 Found (lsomer B) C 72.46 H 10.67 N 10.26

EXAMPLE 8 1 Dodecahydro-S ,9-methano-10-methylbenzocycloocten-l 1-yl)-3-(3-pyridyl)urea A suspension of 10.35 g (30 mM) of 11- aminododecahydro-S ,9-methano- 1 O-methylbenzocyclooctene and 6.0 g (30 mM) 3-pyridyl isocyanate in 375 ml dry benzene was refluxed for 2 hrs. The resulting solution left at RT. overnight. The solid filtered and recrystallized from C H to give 5.1 g (52 percent) of an isomer of the desired product melting at 201 20 7 C. (isomer A). The filtrate was evaporated to dryness and the resulting oil recrystallized from C l-l containing an equal volume of C ll to give 3.1 g (32 percent) of another isomer of the desired compound melting at 153159 C (isomer B). IR (mull) (Isomer A): 3300, 1660, 1590, 1515, 1400, 1230, 760 IR (mull) (Isomer B): 3200, 1630, 1590, 1520, 1400, 1370, 1340, 1320, 1300, 1225, 1180, 795, 745, 705

wherein R is hydrogen or lower alkyl; R is hydrogen or lower alkyl; R is hydrogen or hydroxy; X is oxygen;

andnisl.

2. Dodecahydr0-5,9-methano- 1 O-methylbenzocycloocten-4a,l l-diol l l-(N-methylcarbamate).

3. Dodecahydro-S ,9-methanol O-r'neth cycloocten-4l,l l-diol 1 l-carbamate.

4. 1 ,2,3,4,4a( or ylbenzo l0)5,6,7,8,9-Decahydr0-5,9- methanol O-methylbenzocycloocten- 1 1 -01 carbamate. 

2. Dodecahydro-5,9-methano-10-methylbenzocycloocten-4a,11-diol 11-(N-methylcarbamate).
 3. Dodecahydro-5,9-methano-10-methylbenzocycloocten-41,11-diol 11-carbamate.
 4. 1,2,3,4,4a(or 10)5,6,7,8,9-Decahydro-5,9-methano-10-methylbenzocycloocten-11-ol carbamate. 